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EP3061748A1 - Sonde d'imagerie de la protéine tau - Google Patents

Sonde d'imagerie de la protéine tau Download PDF

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EP3061748A1
EP3061748A1 EP14855618.6A EP14855618A EP3061748A1 EP 3061748 A1 EP3061748 A1 EP 3061748A1 EP 14855618 A EP14855618 A EP 14855618A EP 3061748 A1 EP3061748 A1 EP 3061748A1
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Prior art keywords
group
formula
hydroxy
independently
compound
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German (de)
English (en)
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EP3061748A4 (fr
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Yukitsuka Kudo
Nobuyuki Okamura
Shozo Furumoto
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CLINO Ltd
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CLINO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention relates to a probe for imaging a ⁇ -sheet structure protein which can be used for the diagnosis of conformational diseases, particularly disease (tauopathy) having a cardinal symptom such as intracerebral accumulation of tau protein, for example, Alzheimer's disease.
  • conformational diseases particularly disease (tauopathy) having a cardinal symptom such as intracerebral accumulation of tau protein, for example, Alzheimer's disease.
  • Alzheimer's disease it is known that the accumulation of senile plaque containing amyloid beta-protein (hereinafter referred collectively to as A ⁇ ) as a main component and of neurofibrillary tangles containing hyperphosphorylated tau protein (hereinafter referred collectively to as tau) as a main component proceeds to the degree that it cannot be treated when the specific clinical symptoms of the disease become apparent. In other words, if the current diagnosis of Alzheimer's disease is compared to that of cancer, it is detected only when it has reached the end stage.
  • a ⁇ amyloid beta-protein
  • tau hyperphosphorylated tau protein
  • FIG. 1 the accumulation of A ⁇ is considered to start 10 or more years earlier than that of tau in the brain of Alzheimer's disease.
  • Fig. 1 since the tracing of A ⁇ was considered most appropriate in order to diagnose Alzheimer's disease in the extremely early stage or before its development, almost all PET probes for the diagnosis of Alzheimer's disease were so-called probes for amyloid imaging to trace A ⁇ .
  • [ 11 C] labeled probes were mainly used, but afterwards, the development of [ 18 F] labeled probes that have a long half-life and are easily used in the clinical setting has been attempted.
  • Fig. 2 illustrates the examples of probes for amyloid imaging that has been developed until now.
  • Non-Patent Document 1 images showing administration of PET probes for amyloid imaging of Alzheimer's disease patients were introduced for the first time in the world (refer to Non-Patent Document 1) .
  • amyloid imaging in the diagnosis of Alzheimer's disease would be a so-called versatile diagnostic method that enables the diagnosis of the disease with high sensitivity and specificity, as well as early diagnosis, differential diagnosis, diagnosis of severity (or progress), and preclinical diagnosis (so-called detection of presymptomatic high-risk individuals).
  • Non-Patent Document 4 the ADNI (Alzheimer's Disease Neuroimaging Initiative) held ahead of the International Conference on Alzheimer's Disease in Chicago in July 2008 reported that 53% of healthy elderly were [ 11 C] PIB positive (refer to Non-Patent Document 4) whereas the incidence rate of Alzheimer's disease is considered to be 4 to 6% of the population of 65 or more years old. Although the present inventors think the figure of 53% is an overestimate, the developers of [ 11 C] PIB themselves recognize the possibility of considerable false positives (refer to Non-Patent Document 5).
  • FIG. 3 illustrates the Braak stage of accumulation of A ⁇ and tau in Alzheimer's disease.
  • a ⁇ was considered not to be accumulated (or stage A), while the degree of tau accumulation was stage VI. This implies that in both cases the accumulation of A ⁇ was mild or less, while the accumulation of tau was the highest level of stage VI.
  • Non-Patent Document 7 There were several reports that the histopathology correlating with the clinical symptoms of Alzheimer' s disease was tau rather than A ⁇ in the early 1990s (Non-Patent Document 7). This was unexpectedly reaffirmed by the report by Holmes et al.
  • amyloid (or A ⁇ ) and tau in Alzheimer's disease should be revised to Fig. 4 .
  • Fig. 4 when there is low accumulation of amyloid, MCI and Alzheimer' s disease develop when the tau accumulation reaches the threshold, and when the accumulation of amyloid is very high, MCI and Alzheimer's disease do not develop when the tau accumulation does not reach the threshold. That is to say, the amount of amyloid accumulation is not related to development of MCI and Alzheimer's disease, while tau accumulation defines this development. It is proposed to say "amyloid (or A ⁇ ) has no threshold, but tau has one".
  • tau imaging is probably superior to amyloid imaging, in order to diagnose the severity (or progress) of Alzheimer's disease, or to correctly detect presymptomatic high-risk individuals for Alzheimer's disease.
  • probes for tau imaging are described in, for example, patent literatures 1 to 3, and non-patent literature 8.
  • An object of the present invention is to provide a compound which is highly specific to tau and can image tau with satisfactory sensitivity, and also has high brain transition, low or non-recognized bone-seeking properties and low or undetected toxicity.
  • the present inventors have intensively studied and found a process for preparing a desirable optical isomer with extensively high effectiveness. Also, the present inventors have found that the optical isomer of the compound of a formula (I), a salt thereof or a solvate thereof is a compound which is highly specific to tau and can image tau with satisfactory sensitivity, and also has high brain transition, low or non-recognized bone-seeking properties and low or non-recognized toxicity. They have also found that the compound of a formula (I') can be used as a precursor of the compound of a formula (I), a salt thereof or a solvate thereof.
  • the present invention provides the following:
  • a compound having very high safety which is highly specific to tau and can image tau with satisfactory sensitivity, and also has high brain transition, low or undetected bone-seeking properties and low or undetected toxicity, and a precursor thereof. Accordingly, the diagnosis, the treatment and/or prevention of tauopathy can be carried out using the compound of the present invention. Also, the present invention enables diagnostic imaging of tauopathy, particularly diagnostic imaging using positron emission tomography (PET). Accordingly, the present invention facilitates accurate diagnosis, effective treatment and prevention in the early stages of tauopathy, particularly Alzheimer's disease.
  • PET positron emission tomography
  • the compounds of the present invention are compounds of formulae (I) and (I') described below, or salts or solvates thereof.
  • “compound of the present invention” and “compound according to the present invention” include the compounds of formulae (I) and (I') described below, and salts and solvates thereof, unless otherwise specified.
  • lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,2-dimethyl
  • the lower alkyl group each independently may be optionally substituted with one or more (for example, 1 to 3) substituents selected from halogen and hydroxy.
  • cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • tau protein and “tau” have the same meanings.
  • amyloid ⁇ protein amyloid ⁇ protein
  • a ⁇ protein amyloid ⁇ protein
  • a ⁇ protein amyloid beta protein
  • a ⁇ amyloid beta
  • a ⁇ amyloid beta
  • Non-limiting embodiments of the compound of the formula (I) [wherein the respective symbols are as defined above] are described herein by way of specific examples.
  • Ring A means a formula: wherein, each line that the dotted line intersects with means a bond to the other structural moiety of the above general formula (I). That is, bonds existing at 2- and 5-positions of pyridine ring are respectively attached to R 1 -A- moiety and quinoline ring of the above-mentioned general formula (I). Also, bonds existing at 1- and 4-positions of pyrazole ring are respectively attached to R 1 -A- moiety and quinoline ring of the above-mentioned general formula (I).
  • the ring A is preferably a cyclic group represented by formula:
  • Ring A is unsubstituted, or substituted with one to four (preferably one) R 6 substituents.
  • the R 6 is one or more (preferably one) substituents selected independently from halogen, OH, COOH, SO 3 H, NO 2 , SH, NR a R b , lower alkyl (the alkyl group each independently may be optionally substituted with one or more (preferably two or more) substituents selected from halogen and hydroxy) and -O-lower alkyl (the alkyl group each independently may be optionally substituted with one or more substituents selected from halogen and hydroxy).
  • the R 6 is one or more (preferably one) substituents selected independently from halogen and -O-lower alkyl (the alkyl group each independently may be optionally substituted with one or more (preferably two or more) substituents selected from halogen and hydroxy).
  • the term "lower alkyl group" represented by the R 6 means the same groups as those in the lower alkyl group defined above.
  • a linear or branched alkyl group having 1 to 5 carbon atoms, for exmaple, a methyl group, an ethyl group, a propyl group, and a 1,1-dimethylpropyl group are preferable, and the alkyl group each independently may be optionally substituted with substituent selected from one halogen and one hydroxy.
  • the ring A is unsubstituted or substituted with one substituent selected from fluorine, (3-fluoro-2-hydroxy)propoxy, or (3-fluoro-2-hydroxy)-1,2-dimethyl-propoxy.
  • the R 1 is a group represented by formula: wherein, R 4 and R 5 each independently represents a hydrogen atom, a lower alkyl group (the alkyl group each independently may be optionally substituted with one or more substituents selected from halogen and hydroxy) or a cycloalkyl group,
  • the "lower alkyl group” represented by R 4 and R 5 means the same groups as those in the lower alkyl group defined above. Among these groups, a linear or branched alkyl group having 1 to 3 carbon atoms, that is, a methyl group, an ethyl group and a propyl group are preferable, and the alkyl group each independently may be optionally substituted with one or more substituents selected from halogen and hydroxy.
  • cycloalkyl group represented by R 4 and R 5 means the same groups as those in the cycloalkyl group defined above. Among these groups, a cycloalkyl group having 3 carbon atoms, that is, a cycloalkyl group is preferable.
  • R 4 is a hydrogen atom
  • R 5 is a lower alkyl group (for example, a methyl group, an ethyl group, or a propyl group is preferable, and a methyl group is more preferable).
  • Specific examples of the 3- to 8-membered nitrogen-containing aliphatic ring formed by taking R 4 , R 5 and the nitrogen atom to which they are attached together include, for exmaple, groups of formula: wherein, Z is O, S, CH 2 or NR e , and R e represents a hydrogen atom or a C 1-4 alkyl group.
  • a morpholino group, a piperazine group and a 4-methyl-piperazine group are preferable.
  • Specific examples of the 8- to 16-membered nitrogen-containing fused bicyclic ring formed by taking R 4 and the nitrogen atom to which it is attached together with ring A include groups of formula: wherein, Z is O, S, CH 2 or NR e , and R e represents a hydrogen atom or a C 1-4 alkyl group. Among these groups, a formula: is particularly preferable.
  • R 2 and R 3 each independently represents a halogen atom, OH, COOH, SO 3 H, NO 2 , SH, NR a R b or a lower alkyl group (the alkyl group each independently is substituted with one or more substituents selected from halogen and hydroxy), or a -O-lower alkyl group (the alkyl group each independently may be substituted with one or more substituents selected from halogen and hydroxy).
  • R 1 , R 2 , R 3 and R 6 at least one of the R 1 , R 2 , R 3 and R 6 represents a group represented by formula: wherein,
  • R 1 , R 2 , R 3 and R 6 At least one of the R 1 , R 2 , R 3 and R 6 , for example, the R 2 represents preferably a group represented by the above-mentioned formula: wherein,
  • the group represented by formula: is more preferable.
  • the compound of the present invention is an S-form having as chiral center an asymmetric carbon in the substituent represented by formula:
  • R a and R b each independently represents a hydrogen atom or a lower alkyl group (the alkyl group each independently may be optionally substituted with one or more substituents selected from halogen and hydroxy).
  • Preferred R a and R b is a hydrogen atom.
  • m is an integer of 0 to 4, and preferably 1.
  • n is an integer of 0 to 2, and preferably 0.
  • the compound of the formula (I) is highly specific to tau, and also has high brain uptake, and further any compound not bound to tau rapidly clears from the brain.
  • the compound of the formula (I) is a compound having very high safety, which has low or non-recognized bone-seeking properties and low or non-recognized toxicity. Accordingly, the diagnosis of tauopathy can be carried out using the compound of formula (I) as a probe against tau, and also the treatment and/or prevention of tauopathy can be carried out by using the compound of the formula (I).
  • the compound of formula (I) is suited for imaging diagnosis of tauopathy, particularly imaging diagnosis using PET. Accordingly, it becomes possible to carry out accurate diagnosis, effective treatment and prevention in the early stages of tauopathy, particularly Alzheimer's disease, using the compound of formula (I).
  • a conformational disease is a disease in which a protein having a specific ⁇ -sheet structure accumulates, and there are various diseases characterized by deposition of an insoluble fibrillar protein to various internal organs and tissues.
  • diseases include Alzheimer's disease, Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, prion disease, dementia with Lewy bodies, Parkinson's disease, Huntington's disease, spinal and bulbar atrophy, dentate-rubro-pallido-luysian atrophy, Spinocerebellar Degeneration, Machado-Joseph Disease, Amyotrophic Lateral Sclerosis (ALS), Down's syndrome, Pick's disease, FTDP-17 (Frontotemporal Dementia and Parkinsonism linked to Chromosome 17), LNTD (Limbic Neurofibrillary tangles Dementia), Sudanophilic Leukodystrophy, amyloidosis and the like.
  • PPP progressive supranu
  • the conformational disease preferably means disease (tauopathy) having a cardinal symptom such as intracerebral accumulation of tau protein.
  • Tauopathy includes Alzheimer's disease, Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, and the like.
  • At least one of the R 1 , R 2 , R 3 and R 6 represents a NR a R b (the R a and R b are as the same as defined above, and among them, when they represent an lower alkyl group, they each independently may be optionally substituted with one or more substituents selected from a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a 2-tetrahydropyranyloxy group, an acetoxy group, a halogen atom, a hydroxy group, and a hydroxy lower alkyl group protected with a protecting group for hydroxy), a lower alkyl group (the alkyl group each independently may be optionally substituted with one or more substituents selected from a p-toluenesulfonyloxy group, a methane
  • At least one of the R 1 , R 2 , R 3 and R 6 is -O-lower alkyl (the alkyl group each independently may be optionally substituted with one or more substituents selected from a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a 2-tetrahydropyranyloxy group, an acetoxy group, a halogen atom, a hydroxy group, and a hydroxy lower alkyl group protected with a protecting group for hydroxy).
  • substituents selected from a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a 2-tetrahydropyranyl
  • At least one of the R 1 , R 2 , R 3 and R 6 represents a group represented by formula: or R 1 represents a group represented by formula: wherein, R 5 is the same as defined above.
  • R 2 represents a group represented by formula:
  • the substituent Q is a protecting group for a hydroxy group that has a resistance against a nucleophilic substitution by fluorine anion and may be removed under acidic or alkali condition, and includes, for example, a 2-tetrahydropyranyl (2-THP) group, a methoxymethyl group, a 2-methoxyetoxymethyl group, an ethoxyethyl group, an acetyl group, and a pivaloyl group.
  • 2-THP 2-tetrahydropyranyl
  • the substituent R is a functional group that works as a leaving group against a nucleophilic substitution by fluorine anion, and includes, for example, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a chloromethanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • the compound represented by formula (I') as the precursor of the compound represented by formula (I) of the present invention contains an asymmetric carbon in either a substituent of formula: a substituent of formula: or a substituent of formula: which is thus a S-form compound.
  • n is an integer of 0 to 4.
  • n is an integer of 0 to 2.
  • n is 0.
  • the compound of formula (I') may be used as a precursor of the compound of formula (I). Methods to convert the compound of formula (I') into the compound of formula (I) are well known to persons having ordinary skill in the art, and the compound of formula (I) may be thus easily prepared.
  • Salts of the compound of the present invention are also included in the present invention.
  • the salt can be produced in accordance with a conventional method using the compound of a formula (I) or (I') provided by the present invention.
  • the compound of the formula (I) or (I') has, for example, a basic group derived from an amino group, a pyridyl group and the like in the molecule, the compound can be converted into a corresponding salt by treating with an acid.
  • the acid addition salt examples include hydrohalide salts such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and carbonate; lower alkyl sulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; aryl sulfonic acid salts such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and acid addition salts with amino acids, such as glutamate and aspartate.
  • hydrohalide salts such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide
  • inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and carbon
  • the compound of the present invention when the compound of the present invention has an acidic group such as a carboxyl group in the molecule, the compound can also be converted into a corresponding pharmaceutically acceptable salt by treating with a base.
  • the base addition salt include alkali metal salts such as sodium and potassium; alkali earth metal salts such as calcium and magnesium; ammonium salts; and base addition salts with organic bases such as guanidine, triethylamine and dicyclohexylamine.
  • the compound of the present invention may be present as a free compound, or arbitrary hydrate or solvate of a salt thereof.
  • the protecting group is inserted so as to protect the functional group from an undesirable reaction with a reaction component under the conditions used to perform a desired chemical conversion. Necessity and selection of the protecting group for a specific reaction are known to those skilled in the art, and depend on properties of the functional group to be protected (hydroxy group, amino group, etc.), structure and stability of the molecule with the substituent constituting a part thereof, and reaction conditions. Examples of the protecting group include OTs, OTHP, methoxymethyl and OAc. The protecting group is preferably a protecting group which is eliminated under acidic conditions.
  • the compound of the present invention can be used as a probe without labeling.
  • the presence or absence of the portion to be stained may be examined by bringing the compound of the present invention into contact with a biopsy tissue sample.
  • labeled compound of the present invention as a probe for the diagnosis of tauopathy.
  • Examples of label include a fluorescent substance, an affinity substance, an enzyme substrate, a radioactive nuclide and the like.
  • a probe labeled with a radioactive nuclide is usually used in diagnostic imaging of tauopathy. It is possible to label the compound of the present invention with various radioactive nuclides by the methods which are well known in the art.
  • 3 H, 14 C, 35 S, 131 I and the like are radioactive nuclides which have been used for a long time, and are often utilized in vivo.
  • General requirements for diagnostic imaging probes and means for their detection are to permit in vivo diagnosis, to cause less harm to patients (particularly, to be non-invasive), to have a high sensitivity of detection, to have an appropriate half-life (to have an appropriate period of time for preparing the labeled probes and for diagnosis) and the like.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • PET which detects two ⁇ -rays emitting in opposite directions from a positron emitting nuclide by means of simultaneous counting with a pair of detectors, provides information which is excellent in resolution and quantification and thus is preferable.
  • the compound of the present invention can be labeled with a ⁇ -ray emitting nuclide such as 99m Tc, 111 In, 67 Ga, 201 T1, 123 I, 133 Xe and the like. 99m Tc and 123 I are often used for SPECT.
  • the compound of the present invention can be labeled with a positron emitting nuclide such as 11 C, 13 N, 15 O, 18 F, 34m Cl, 45 Ti, 48 V, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 76 Br, 89 Zr, 94m Tc, and 124 I and the like.
  • positron emitting nuclides 11 C, 13 N, 15 O and 18 F are preferable, 18 F and 11 C are more preferable, 18 F is particularly preferable, from the viewpoint of having an appropriate half-life, the ease of labeling and the like.
  • labeling the compound of the present invention with a radiation emitting nuclide such as a positron emitting nuclides or ⁇ -ray emitting nuclide
  • labeling may preferably be carried out at an alkyl group and on phenyl ring in the compound.
  • Such labeled compounds of the present invention are also included in the present invention.
  • any position of the side chain may be labeled with 18 F, or hydrogen on the ring may be substituted with 18 F.
  • hydrogen contained in any one of alkyl substituents may be substituted with 18 F.
  • Radionuclides used in the compounds according to the present invention are generated on an instrument termed cyclotron or generator.
  • a person with an ordinary skill in the art can select methods and instruments for production depending upon nuclides to be produced. Nuclides thus produced can be used to label the compounds of the present invention.
  • Typical methods include chemical synthesis, isotope exchange, and biosynthesis processes.
  • Chemical synthesis processes have been traditionally and widely employed, and are essentially the same as usual chemical synthesis processes, except that radioactive starting materials are used.
  • Various nuclides are introduced into compounds by these chemical processes.
  • Isotope exchanging processes are processes by which 3 H, 35 S, 125 I or the like contained in a compound of a simple structure is transferred into compound having a complex structure, thereby obtaining a compound having a complex structure that has been labeled with these nuclide.
  • Biosynthesis processes are processes by which a compound labeled with 14 C, 35 S or the like is given to cells such as microorganisms to obtain its metabolites having these nuclide introduced therein.
  • 18 F a chemical form as fluorine anion, which can be prepared in large amount thereof by cyclotron with high specific radioactivity, is often used in a labeling synthesis, and a salt of 18 F anion with increased nucleophilicity is used as a labeling agent in a nucleophilic substitution with a compound having a leaving group (label precursor) to give the 18 F labeled compound of the present invention.
  • the nucleophilic substitution is preferably carried out in an organic solvent, and is more preferably reacted in anhydrous high polar solvent (such as DMSO, acetonitrile, and DMF).
  • the reaction temperature is not particularly limited, and may either be at room temperature or with heating, for example, a temperature near the boiling point of the used reaction solvent.
  • the reaction period may be within a range of a few minutes to a few days, and the reaction may be achieved, for example, within a range of a few minutes to a few hours.
  • the step comprising introduction of the radionuclide should be as close as possible to the end of the radiosynthesis.
  • the protecting group for hydroxy group in the obtained product may be removed under acidic or alkali condition to obtain the desired 18 F - labeled compound.
  • the solution comprising the 18 F - labeled compound of the present invention may be contacted with an ion-exchange resin supported by 18 F - to obtain 18 F - labeled compound of the present invention.
  • positron emitting nuclides such as 11 C, 13 N, 15 O and 18 F, which have relatively short half-lives
  • the labeled compound of the present invention may be administered to subjects locally or systemically.
  • Routes for administration include intradermal, intraperitoneal, intravenous, intra-arterial injections or infusions into the spinal fluid and the like, and can be selected depending on factors such as the disease type, nuclide used, compound used, the condition of the subject, the site to be examined.
  • the site to be examined can be investigated with means such as PET, SPECT by administering the probe of the present invention, followed by the elapse of a sufficient time to allow its binding to tau protein and decay. These procedures can be selected as appropriate depending on factors such as the disease type, nuclide used, compound used, the condition of the subject, the site to be examined.
  • the dose of the compound of the present invention which has been labeled with a radionuclide, varies depending on the disease type, nuclide used, compound used, the age, physical condition, and gender of the subject, the degree of the disease, the site to be examined and the like. In particular, sufficient care has to be taken in connection with radioactive exposure to the subject.
  • the amount of radioactivity of the compound labeled with a positron emitting nuclide such as 11 C, 13 N, 15 O and 18 F of the present invention is usually within a range from 3.7 megabecquerels to 3.7 gigabecquerels, and preferably from 18 megabecquerels to 740 megabecquerels.
  • the compound of the present invention or a salt or solvate thereof is suited for use in a treatment method of tauopathy, a diagnosis method, a composition for treatment, a composition for diagnosis, a kit for diagnosis, use for the production of these compositions and kits, and other uses, which will be described below.
  • the compounds or salts or solvates thereof exemplified in the above description about the compounds of formulae (I) to (VI) are preferable, and those included in the compound of formula (I) or a salt or solvate thereof are particularly preferable.
  • a compound of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 represents formula: wherein, each symbol is as the same as defined above, preferably, a compound represented by formula: particularly preferably, a compound represented by formula: has a property in which a transition into brain is excellent and also non-binding compound disappears rapidly from the brain, and thus the positron nuclide, preferably the 18 F labeled compound is suited as a PET probe for sensitively imaging tau protein accumulated in the brain.
  • These compounds are also suited for administration to the human body because of considerably less or scarce accumulation in bone.
  • the present invention provides a composition containing the compound of the present invention for diagnostic imaging of tauopathy.
  • the composition of the present invention contains the compound of the present invention and a pharmaceutically acceptable carrier. It is preferred that the compound of the present invention in the composition is labeled. Although various labeling methods are possible as described above, labeling with radionuclides (in particular, positron emitting nuclides such as 11 C, 13 N, 15 O and 18 F for PET) is desirable for in vivo image diagnosis applications. It is preferable from their purposes that the form of the composition of the present invention is one allowing injection or infusion.
  • a pharmaceutically acceptable carrier is preferably liquid and examples thereof include, but are not limited to, aqueous solvents such as potassium phosphate buffer, physiological saline, ringer solution and distilled water; and non-aqueous solvents such as polyethylene glycol, vegetable oil, ethanol, glycerin, dimethyl sulfoxide and propylene glycol.
  • a mixing ratio of the carrier to the compound of the present invention can be appropriately selected depending on the site of application, detection means and the like, and is usually from 100,000 : 1 to 2:1, and preferably from 10,000: 1 to 10: 1.
  • composition of the present invention may further contain known antimicrobials (for example, antimicrobial drug, etc.), local anesthetics (for example, procaine hydrochloride, etc.), buffers (for example, Tris-hydrochloride buffer, HEPES buffer, etc.), osmolytes (for example, glucose, sorbitol, sodium chloride, etc.) and the like.
  • antimicrobials for example, antimicrobial drug, etc.
  • local anesthetics for example, procaine hydrochloride, etc.
  • buffers for example, Tris-hydrochloride buffer, HEPES buffer, etc.
  • osmolytes for example, glucose, sorbitol, sodium chloride, etc.
  • the present invention provides a kit for image diagnosis of tauopathy, containing the compound of the present invention as the essential ingredient.
  • the kit is a package in which each of the components such as the labeled compound of the present invention, or its labeled precursor, a solvent for dissolving the compound, a reagent used for labeling synthesis or a solution of the same, a buffer, an osmoregulatory agent, an antimicrobial, a local anesthetic, a solubilizing agent, a radiolysis- preventing agent are packaged separately into respective containers, or some of the components are packaged together into respective containers.
  • the compound of the present invention may be unlabeled or labeled.
  • kits may contain a labeled precursor of the present invention, and the labeled compound of the present invention can be prepared using the labeled precursor by a labeling synthesis, prior to use, according to usual methods as described above.
  • the compound of the present invention may be presented as a solid, such as a lyophilized powder, or in solution in appropriate solvents. Solvents may be similar to carriers used in the above composition of the present invention.
  • Each of the components such as a buffer, an osmoregulatory agent, an antimicrobial, a local anesthetic, also may be similar to those used in the above composition of the present invention.
  • kits can be selected as appropriate, they may be of shapes suitable for carrying out the introduction of a label into the compound of the present invention, or of light-shielding materials, depending on the nature of compounds, or take forms such as vials or syringes, so as to be convenient for administration to patients.
  • the kit may also contains, as appropriate, container or instruments for labeling synthesis, such as vials, syringe, three-way stopcock, needle, solid-phase extraction cartridge, sterilizing filter and the others.
  • the kit may further contains, as appropriate, tools necessary for diagnosis, for example, syringes, an infusion set, or device for use in a PET or SPECT apparatus.
  • the kit usually has its instructions attached thereto.
  • the compounds of the present invention specifically bind to tau protein, and thus can be also used, for example, for detecting and quantifying tau protein with or without labeling by contacting with sample specimens in vitro.
  • the compounds of the present invention can be used for staining tau protein in microscopic specimens, for colorimetric determination of tau protein in samples, or for quantifying tau protein using a scintillation counter. Preparation of a microscope specimen and staining using the compound of the present invention can be carried out by a conventional method known to a person with an ordinary skill in the art.
  • the compounds of the present invention are highly specific to tau protein. Therefore, the compounds of the present invention are useful, for example, for studies of disease with tau protein accumulation or in their diagnosis before and after death, and could be useful, for example, as agents for staining neurofibrillary tangles in brain sections of Alzheimer's disease patients. Staining of specimens, for example, brain sections using the compounds of the present invention can be carried out in a conventional method known to a person of ordinary skill in the art.
  • a compound represented by formula: has a property in which a transition into brain is excellent and also non-binding compound may be disappeared rapidly from the brain, and an accumulation into brain is thus low, and also an accumulation into bone is considerably less or scarce. Accordingly, these compounds of the present invention are not only considerably safe probes for the diagnosis of tauopathy, but also exhibit high safety even when used as remedies or preventives described hereinafter.
  • the present invention is directed to a composition for staining of amyloid ⁇ protein, particularly tau in a sample, containing the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a kit for staining of amyloid ⁇ protein, particularly tau in a sample, containing the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as essential ingredients. Furthermore, the present invention is directed to a method of staining amyloid ⁇ protein, particularly tau in a sample, the method comprising using the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Samples suited for above staining are brain sections.
  • the compound of the present invention serves as remedies or preventives for causes of a disease, particularly tauopathy, for example, Alzheimer's disease since protein itself has a ⁇ -sheet structure.
  • the present invention provides:
  • Such pharmaceutical compositions are not limited in particular, but liquid formulations, particularly formulations for injection, are preferable.
  • Such formulations for injection can be infused directly into the brain, or alternatively the above pharmaceutical compositions can be formulated for intravenous injection or drip and administered, since the compounds of the present invention have high permeability through the blood-brain barrier, as shown in the Examples.
  • Such liquid formulations can be prepared by methods well known in the art. Solutions can be prepared, for example, by dissolving the compound of the present invention in an appropriate carrier, water for injection, physiological saline, Ringer's solution or the like, sterilizing the solution through a filter or the like, and then filling the sterilized solution into appropriate containers, for example, vials or ampules.
  • Solutions also can be lyophilized and when used, reconstituted with an appropriate carrier.
  • Suspensions can be prepared, for example, by sterilizing the compound of the present invention, for example, by exposure to ethylene oxide, and then suspending it in a sterilized liquid carrier.
  • an injection can be prepared by adding a solubilizing agent to a quinoline derivative according to the present invention.
  • solubilizing agent nonionic surfactants, cationic surfactants, amphoteric surfactants and the like used in the art.
  • solubilizing agents Polysorbate 80, polyethylene glycol, ethanol or propylene glycol is preferable, and Polysorbate 80 is more preferable.
  • the amount of the compounds of the present invention to be administered to a human subject in the above treatment method, prevention method and use varies depending on the condition, gender, age, weight of the patient and the like, and is generally within a range from 0.1 mg to 1 g, preferably from 1 mg to 100 mg, and more preferably from 5 mg to 50 mg, per day for adult humans weighing 70 kg. It is possible to conduct a treatment with such a dose for a specified period of time, followed by increasing or reducing the dose according to the outcome.
  • the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can also be used as a probe for the diagnosis of conformational disease, particularly tauopathy, preferably an image diagnosis probe labeled with a radiation nuclide. Furthermore, the compounds of the present invention have the effect for the treatment and/or prevention of conformational disease, particularly tauopathy.
  • the present invention is also directed to:
  • the dose of the compounds of the present invention to be administered to a human subject in the above treatment methods and prevention methods is as described above.
  • the present invention provides a kit for preparing a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, the kit comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, a labeling agent, and optionally instructions for labeling the compound.
  • the labeling agent is, for example, a radioactive nuclide or a positron emitting nuclide.
  • the radioactive nuclide is, for example, a ⁇ -ray emitting nuclide.
  • the positron emitting nuclide is selected from, for example, the group consisting of 11 C, 13 N, 15 O, 18 F, 35m Cl, 76 Br, 45 Ti, 48 V, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 89 Zr, 94m Tc and 124 I.
  • the positron emitting nuclide is 11 C or 18 F.
  • the labeling agent is an agent in which the radioactive nuclide has such chemical form as being suitable for labeling the compound, and is known to those skilled in the art.
  • the optically active compound of the present invention can be prepared stereo specifically by using a chiral synthon having an optical activity of the compound of the present invention.
  • examples of the chiral synthon that can be used in a preparation of the compound of the present invention are shown.
  • the chiral synthon can be prepared according to a general chemical synthesis method in an organic chemical field, or can be obtained as a commercial reagent.
  • a chiral synthon is derivatized to a compound of formula (II) that can offer an optical activity of the compound of the present invention.
  • step i) the compound of formula (II) is reacted with a compound of formula (V) to prepare an intermediate compound of formula (V) (step i)).
  • a step of binding reaction of the chiral synthon to the compound of formula (V) may be carried out to convert the structure of a chiral side chain of the resulting compound into a compound of formula (V').
  • the resulting compound may be reacted with the boron compound having -A-R 1 group that represented by formula (VI) or formula (VII) to prepare a desired compound of formula (I) or formula (I') (step ii)).
  • a procedure in each reaction step can be carried out according to a reaction condition (for example, reagent, reation temperature, reaction period) that is generally known in an organic chemical field.
  • a reaction condition for example, reagent, reation temperature, reaction period
  • reaction sequences of the step i) and the step ii) in the above-mentioned process may be reversed.
  • a chiral synthon is derivatized to a compound of formula (II) that can offer an optical activity of the compound of the present invention.
  • intermediate compound of formula (V'') may be reacted with the compound of formula (II) to prepare the desired compound of formula (I) or formula (I') (step ii)).
  • a procedure in each reaction step can be carried out according to a reaction condition (for example, reagent, reation temperature, reaction period) that is generally known in an organic chemical field.
  • a reaction condition for example, reagent, reation temperature, reaction period
  • effects such as a reduction in the number of reaction steps and an increase in yield through the overall synthesis steps.
  • THK-5105S One example of a synthesis of THK-5105S is shown below. Synthesis of THK-5105S
  • chloroform 18 mL
  • trifluoroacetic acid 12 mL
  • water 3 mL
  • the mixture was stirred at room temperature for 16 hours.
  • water and ethyl acetate was adjusted with aqueous potassium carbonate solution to pH 8, and extracted with ethyl acetate.
  • optically active compounds can be also obtained by separating the racemic form using an optical resolution method that is generally known in an organic chemical field.
  • optical resolution method include an optical resolution by chromatography with an optically active column, a preferential crystallization, diastereomeric salt formation method, and optical resolution.
  • optically active column include commercially available chiral column.
  • the racemic form of the compound of the present invention can be prepared according to WO 2012/057312 .
  • the reference examples are shown in Tables 2-1 to 2-17 below.
  • Table 2-1 THK-5004 2-(4-aminophenyl)-8-( 1-fluoromethyl-2-hydr oxyethoxy)quinoline THK-5035 2-(4-diethylaminophen yl)-6-(1-fluoromethyl -2-hydroxy)quinoline THK-5038 2-(4-diethylaminophen yl)-7-(2-fluoromethyl -2-hydroxyethoxy)quin oline THK-5051 2-(4-diethylaminophen yl)-8-(1-fluoromethyl -2-hydroxyethoxy)quin oline Table 2-2 THK-5058 2-(4-diethylaminophe nyl)-7-(1-fluorometh yl-2-hydroxyethoxy)q uinoline THK-5059 2-(4-die
  • CHIRALPAK IA-3 manufactured by Daicel Chemical Industries, Ltd.
  • flow rate 0.5 mL/min
  • Absorbance measurement wavelength 315 nm
  • a DMSO solution (0.70 mL) containing THK-5121S (2.0 mg), as a label precursor, dissolved therein was added, followed by heating and stirring in the oil bath (110°C) for 10 minutes. Thereafter, thereto was added hydrochloric acid (2M, 0.2 mL), and the mixture was reacted at 110 °C for another 3 minutes, and the reaction solution was diluted with potassium acetate solution (4M, 0.1 mL) and distilled water (7.0mL), and loaded into a Sep-Pack tC18 cartridge (manufactured by Waters) and, after washing the cartridge with distilled water, the crude product was eluted with ethanol.
  • test example of the label compound of the present invention is shown.
  • the preparative HPLC fraction of [ 18 F] THK-5105S which was synthesized according to the synthesis procedure described above, was diluted with distilled water, and then subjected to solid-phase extraction using a Sep-Pak tC18 cartridge, followed by elution with ethanol or DMSO and appropriate dilution, and used in binding tests and autoradiography experiments.
  • Polysorbate 80 was added to the ethanol-eluted fraction, from which the ethanol was removed using an evaporator.
  • the [ 18 F] THK-5105S containing radioactive residue within the flask was dissolved in physiological saline and the solution prepared was used as a solution for injection.
  • [ 18 F] THK-5105 (R)-enantiomer [ 18 F] THK-5105R), [ 18 F] THK-5117S (S- form of THK-5117), [ 18 F] THK-5117R (R- form of THK-5117), [ 18 F] THK-5151S (S- form of THK-5151), and [ 18 F] THK-5151R (R- form of THK-5151) was similarly synthesized from each corresponding label precursors, and used in a biological evaluation experiment.
  • a brain specimen in hippocampus of the patient which was definitively-diagnosed as Alzheimer's disease pathologically was used.
  • a paraffin-embedded brain tissue was sliced by 6 ⁇ m or 8 ⁇ m thick, and stretched on a glass slide, and dried.
  • the paraffin brain sections were deparaffinized by washing sequentially with xylene 10 min. ⁇ 2, 100% ethanol 5 min. ⁇ 2, 90% ethanol 5 min., and flowing water 10 min. After deparaffinization, the sections were immersed in PBS.
  • Each of about 400 ⁇ Ci/ml of [ 18 F]THK-5105S and [ 18 F]THK-5105R was added dropwise to the sections, and the sections were allowed to a reaction at room temperature for 10 min.
  • the sections were immersed in distilled water for 2 min., and successively, shaked lightly in 50% EtOH for 2 min., and thereafter immersed in distilled water for 2 min. again, and dried on paraffin stretching plate. Then, the sections were contacted with imaging plate, and allowed to stand overnight, and on next day, the imaging was read on BAS5000 (manufactured by FUJIFILM Holdings Corporation).
  • Figure 5 shows autoradiography imaging in each hippocampus section.
  • [ 18 F] THK-5105S and [ 18 F] THK-5151S were clearly found to give stronger imaging signal in comparison with the corresponding [ 18 F] THK-5105R and [ 18 F] THK-5151R in tau lesion region, which means that they binds more strongly to tau pathology.
  • THK-5105S or THK-5105R was used as an assay buffer, and the concentration of THK-5105S or THK-5105R was adjusted with 2nM [ 3 H] THK-5117 to 10 -5 to 10 -10 M in a reaction system (200 ⁇ L) containing 100 ⁇ g of the homogenates, and the competitive tests were then carried out.
  • a nonspecific binding was measured with 2 ⁇ M of THK-5117.
  • a glass filter plate was used to separate [ 3 H] THK-5117 bound to the homogenates and unbound [ 3 H] THK-5117, and the filter plate was washed, and then to the separated filter was added liquid scintillation cocktail, and the bound radioactivity was measured on a liquid scintillation counter.
  • the data was analyzed by analysis software GraphPad Prism (Ver. 5). The competitive tests were carried out similarly on THK-5117S, THK-5117R, THK-5151S, and THK-5151R.
  • the reaction system was adjusted such that the tissue concentration was made 100 ⁇ g and [ 18 F]THK-5105S concentration was made 1 nM, and the binding test (1 hour incubation) was carried out in the reaction system.
  • the binding test was carried out also on [ 18 F] THK-5105R according to the similar method.
  • the tau concentration or A ⁇ concentration was plotted on horizontal axis Vertical axis, and the bound amount of [ 18 F] THK-5105S and [ 18 F] THK-5105R was plotted on vertical axis, and the correlation thereof was evaluated.
  • each saturation binding experiment of [ 18 F] THK-5151S and [ 18 F ] THK-5151R was carried out with AD hippocampus tissue homogenate.
  • Zero point one (0.1) to 100 nM of each tested substance was incubated with hippocampus homogenate, and then filtered with a filter, washed, and then measured radioactivity supplemented by the filter, and thereby calculated as total binding and nonspecific binding at each concentration.
  • the data was analyzed with GraphPad Prism (Ver. 5) to calculate binding dissociation constants Kd and Bmax.
  • the binding curve of the results and the analysis results are shown as Figure 6c .
  • [ 18 F] THK-5151S showed about one tenth small Kd value, and showed about fourth times large Bmax/Kd value as bonding potential, in comparison with those of [ 18 F] THK-5151R. Thus it was found that a binding affinity with tau lesion of [ 18 F] THK-5151S is superior to that of [ 18 F] THK-5151R.
  • 35 frames (10 ⁇ 60 s, 10 ⁇ 120 s, 10 ⁇ 300 s, 5 ⁇ 480 s) were reconstructed, and a region of interest was set in the brain, and quantified as SUV, and a time-activity curve (TAC) was created, and the Dynamism of the both probes were compared.
  • TAC time-activity curve
  • a saline comprising [ 18 F] THK-5105S or [ 18 F] THK-5105R was administered intravenously via tail to ICR mouse (male 6 to 7 weeks old), and the time change of radioactivity distribution in brain was measured on Clairvivopet/CT (manufactured by Shimadzu Corporation, Kyoto). The brain dynamics was evaluated by the time-change of the accumulation rate of radioactivity in brain tissue after 2 min., 10 min., 30 min., 60 min., and 120 min.
  • the accumulation rate of radioactivity was calculated as the ratio of radioactivity per weight of evaluated tissue against total administered radioactivity (% Injected Dose/g of tissue; % ID/g).
  • the measurement of the radioactivity was carried out with Gamma counter (Accuflex ⁇ 7000, measured by Hitachi-Aloka Medical, Tokyo).
  • the experimental procedure was as follows. After administering the label compound intravenously via tail at 2 min. , 10 min., 30 min., 60 min., and 120 min., cervical dislocation of mouse was performed under ether anesthesia, and organ tissues were extracted. The radioactivity and the weight of each sample were measured, and the data was analyzed to calculate %ID/g. Also, as the evaluation index for the disappearance from the brain, the divided value of the accumulation rate at 2 min. after administration by the accumulation rate at 60 min. after administration (2 min. /60 min. ratio) was calculated. This means that higher value represents more superior disappearance from the brain. The above results are shown in Table 5.
  • the compounds of the present invention are very useful, for example, in early detection, treatment and prevention of neurofibrillary tangles including Alzheimer's disease, and can be utilized in the fields of the production of diagnostic agents and diagnostic kits for these diseases, the fields of the production of remedies and preventatives for these diseases, studies of these diseases and the like.

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CN107488144B (zh) * 2017-08-09 2021-06-04 复旦大学 一种可以特异性结合并能抑制Tau蛋白聚集的分子及其制备方法和应用
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AU2014338155A1 (en) 2016-05-19
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SG11201603131RA (en) 2016-05-30
RU2016119524A (ru) 2017-11-28
AU2014338155B2 (en) 2018-08-23
SG10201803294PA (en) 2018-06-28
WO2015060365A1 (fr) 2015-04-30
JPWO2015060365A1 (ja) 2017-03-09
EP3061748A4 (fr) 2017-04-05
BR112016008871A8 (pt) 2020-03-24
IL245221A0 (en) 2016-06-30
MX2016005233A (es) 2017-01-05
KR20160072226A (ko) 2016-06-22
US20160244411A1 (en) 2016-08-25
RU2016119524A3 (fr) 2018-06-14

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